Current estradiol therapy includes oral, transdermal, injectable and vaginal formulations. Transdermal delivery comprises patches, gels, lotions and sprays, while vaginal products include suppositories, creams, and rings.
Estradiol, when taken orally as tablets, pills or capsules, is converted for a large part to estrone after absorption in the gastrointestinal tract and metabolism in the liver (first-pass metabolism). This causes an imbalance in the estradiol/estrone ratio, which is normally 1:1 in premenstrual women. This imbalance is mainly responsible for a change in lipids and clotting factors. Non-oral products (transdermal, vaginal) avoid this hepatic first-pass metabolism and therefore are considered first choice in estradiol suppletion.
In general, it is advisable to use the lowest dose of the hormone estradiol possible, because overdosing may lead to side effects related to unphysiological hormone levels. Low-dose non-oral products are first choice because of (1) the low-dose administered, (2) the physiological ratio between levels of estradiol and its metabolite estrone, and (3) as a consequence the decreased risk of adverse effects. The use of very low doses may also be beneficial as opposed treatment (continuous or cyclic co-administration of a progestogen) is not an absolute requirement because the endometrium does not proliferate upon administration of very low doses of estradiol.
In the research into new estradiol products, non-oral administration has been considered, including products for nasal and oromucosal administration. U.S. Pat. No. 5,955,098 discloses a buccal aerosol spray, comprising a propellant 50-95%, a non-polar solvent 5-50%, the active drug compound 0.001-15% (including estradiol), and a flavoring agent 0.05-5%. U.S. Pat. No. 6,110,486 discloses a buccal spray containing estradiol, dissolved in a pharmacologically acceptable polar solvent, comprising in weight % of total composition: polar solvent 75-99.8%, active compound 0.68-40%. As solvents for the sprays there are used low molecular weight polyethylene glycols (PEG) of 200-1000 MW (preferably 200-600) and also low molecular weight alcohols and polyols, such as glycerin and water. Illustrated is a spray formulation containing estradiol and 85% polyethylene glycol. However, this solvent has a bitter, burning taste in the mouth, making a spray, based mainly on such an ingredient, poorly acceptable for chronic use.
US 2011/0097405 discloses an oromucosal estradiol product, which is absorbed mainly in the oral cavity and not in the gastro-intestinal tract. It is a water-soluble film, called wafer. Such wafers containing estradiol in a low dose dissolve quickly in the mouth, thereby releasing estradiol, which then can be absorbed via the oromucosal route. Buccal tablets comprising estradiol are disclosed in EP 0 371 466 and WO 2010/089078. Medicated papers for oromucosal administration containing estradiol and a cyclodextrin are described in EP 1 867 321.
Formulations of dimethyl-β-cyclodextrin complexes of 17β-estradiol and/or progesterone in an aqueous solution for nasal application have been described in EP 0349091. One such formulation containing 17β-estradiol complexed in methylated-β-cyclodextrin has been authorized for medical use under the trade name Aerodiol™. This nasal spray product, administered in a low dose of 300 μg/day, was as effective as a 2 mg oral tablet/day in treating menopausal symptoms. It showed reduced adverse effects, i.e. fewer incidences of mastalgia and withdrawal bleedings. Furthermore, beneficial effects on some lipid parameters, on markers of bone resorption, bone formation and bone mineral density were reported. Finally, less breast tenderness was found with intranasal administration of estradiol as compared to oral treatment.
Because of the side effects of frequent nasal administration, Aerodiol™ is recommended for once daily administration in a high dose resulting in high peak estradiol levels. These are reached within 10-30 min. and the levels return to 10% of the peak value in about two hours after administration (Devissaguet et al., Eur. J. Drug Metabol. Pharmacokinetics 1999; 24: 265-271). This means that once daily intranasal administration of Aerodiol™ results in a “pulsatile” profile, comprising one large peak per day, followed by a period during which estradiol levels remain at a low level. Peak levels after administration of 300 μg estradiol by the required quantity of Aerodiol™ nasal spray reach values of 1400 pg/l. Normal estradiol levels differ slightly per laboratory, but range from 100-500 pg/ml during a menstrual cycle. This means that the peak level of 1400 pg/ml, obtained with nasal Aerodiol™, is about 3 times higher than the highest normal levels in premenopausal women.
A further disadvantage related to nasal administration is that the access to the nasal mucosa can be compromised in instances such as common cold or allergy resulting in a running or blocked nose. This results in inconsistent or even no nasal absorption. The product characteristics of Aerodiol™ teach that in that instance the patient, should administer a double dose of Aerodiol™ via the oromucosal route to reach similar estradiol serum levels.
Moreover, nasal administration may give rise to local side effects in the nose, such as local irritation, itching, rhinorrhoea, sneezing and nosebleeds. Multiple nasal administrations increase these undesired side effects.
It is a first object of the invention to avoid nasal administration of estradiol and the side effects associated therewith.
It is a second object of the invention to provide an estradiol composition for oromucosal administration that does not require the administration of high doses of estradiol, such as for example the double dose required for oromucosal administration of Aerodiol™.
Further, it is an object of the invention to provide a new dosage regimen for estradiol administration that provides a physiological pharmacokinetic profile approaching normal estradiol plasma levels. A particular object is the provision of a dosage regimen with low estradiol peak levels, in particular a regimen that keeps the highest estradiol levels under 500 pg/ml, and avoids the high peak serum levels seen with the administration of existing nasal formulations.
It is also an object of the invention to provide a new and improved dosage form comprising a low dose estradiol formulation, for application to the oral mucosa, that (1) delivers a similar or better bioavailability than nasal administration, (2) provides a dosage form whereby the dose can be individualized, (3) with a flexible dosage frequency and (4) offers better patient compliance.